There is growing evidence that genes involved with innate immunity and inflammation may impact the risk of prostate cancer, as well as progression of the disease. During the initial funding period of this project we have successfully undertaken a number of complementary studies to investigate some of these candidate genes. Our preliminary results suggest that prostate cancer may be affected by variants in genes involved in the innate immune response and inflammation pathway (i.e., in RNASEL, OAS1, TNF-a, and LTA). We propose building on these findings by comprehensively evaluating the impact of candidate genes involved in this pathway on prostate cancer development and progression. Specifically, we first aim to evaluate the association between prostate cancer and single nucleotide polymorphisms and haplotypes in the following 23 candidate genes: Macrophage Scavenger Receptor 1, Toll-like Receptors 1, 2, 4, 5, 6, and 10, Ribonuclease L.,2',5'Oligoadenylate Sythetase 1 and 2, Interleukin 8, 1 Beta, and 1RN, Macrophage Migration Inhibitory Factor, Tumor Necrosis Factor Alpha, Lymphotoxin Alpha, Macrophage-lnhibitory-Cytokine-1, Cyclooxygenase-2, and five genes in the Nuclear Factor kappa- Beta Pathway. This study will use an existing population recruited during the initial funding period of this grant (N=1,454;727 cases, 727 matched controls). Cases are men diagnosed with more clinically relevant disease (i.e., Gleason score >. 7, tumor-node-metastasis (TNM) stage >T2c, or prostate-specific antigen (PSA) >10), making this population ideally suited for studying both risk of prostate cancer and disease progression. Therefore, our second aim-is to collect prospective information on the course of the case's disease (e.g., post-treatment PSA levels), and then evaluate the relationship between these candidate genes and prostate cancer progression. Studying the same genes in these two aims will allow us to distinguish whether they are involved in prostate cancer risk and/or progression. Our final aim is to synthesize information on the candidate genes studied here by investigating their joint and interactive effects on prostate cancer development and progression with a novel hierarchical model. Determining the impact of candidate genes involved with the innate immunity and inflammation pathway on prostate cancer development and progression may have a significant impact on the public's health. In particular, the knowledge from this study may give important insights into the underlying mechanism of disease, provide a valuable screening tool for non-diseased men, and help guide treatment plans among men diagnosed with prostate cancer.